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The preparation method of neratinib

A compound and molar ratio technology, applied in the field of preparation of the anticancer drug Neratinib, can solve the problems of high toxicity, environmental pollution and high cost

Active Publication Date: 2016-06-22
CHIA TAI TIANQING PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] All have (E)-4-dimethylamino-2-butenoyl chloride condensation reaction to generate amide in above-mentioned synthetic route, this step reaction will use expensive (E)-4-dimethylamino-2-butenoic acid And highly corrosive and highly toxic oxalyl chloride, the preparation of easily degradable acid chloride is not conducive to large-scale production and brings serious environmental pollution
[0007] CN102020639A discloses a method for synthesizing Neratinib analogs by Wittig-Hornor reaction, but the reaction uses expensive and toxic bistrimethylsilylamide lithium, and the reaction must be carried out at low temperature
[0008] The invention provides a method for synthesizing Naratinib. The method of the invention has high yield and mild reaction conditions. The reagents used are commonly used commercially available reagents with low price, which can avoid the high cost and high toxicity of the traditional route. problems, more suitable for industrial production, with good economic prospects

Method used

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  • The preparation method of neratinib
  • The preparation method of neratinib
  • The preparation method of neratinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] The synthesis of embodiment 1Neratinib

[0023] N 2 Under protection, 11.7mL (0.07mol) of 6mol / L hydrochloric acid was cooled to 0°C, 9.1mL (0.05mol) of dimethylaminoacetaldehyde diethyl acetal was added dropwise, hydrolyzed at 40°C for 12 hours, cooled to 0°C, and set aside Solution A).

[0024] Add N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinone in sequence to 150mL absolute ethanol Phenyl]-2-diethyl phosphate-acetamide 12.5g (0.02mol), lithium chloride 0.85g (0.02mol), lower the temperature to 0°C, add sodium ethoxide 4.1g (0.06mol), stir for 0.5h, drop Add stock solution A, and continue to react for 40 minutes after dropping. Add 500 mL of ethyl acetate, filter, and add 500 mL of water to the filtrate. Separate the organic layer, extract the aqueous layer with 2×200 mL ethyl acetate, combine the organic layers, wash with water, wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrate to dryness under reduced pre...

Embodiment 2

[0027] The synthesis of embodiment 2Neratinib

[0028] Add N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl successively to 150mL methanol ]-2-diethyl phosphate-acetamide 12.5g (0.02mol), lithium chloride 0.85g (0.02mol), cooled to -10°C, added sodium methoxide 5.4g (0.1mol), stirred for 0.5h, added dropwise The standby solution A described in Example 1 continued to react for 40 minutes after dropping. Add 500 mL of ethyl acetate, filter, and add 500 mL of water to the filtrate. Separate the organic layer, extract the aqueous layer with 2×200 mL ethyl acetate, combine the organic layers, wash with water, wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrate to dryness under reduced pressure and recrystallize from acetonitrile / THF to obtain 9.5 g of light yellow solid with a yield of 85.1%.

Embodiment 3

[0029] The synthesis of embodiment 3Neratinib

[0030] Add N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolone successively to 50mL isopropanol Phenyl]-2-diethyl phosphate-acetamide 1.25g (0.002mol), lithium chloride 0.17g (0.004mol), lower the temperature to 0°C, add sodium isopropoxide 0.82g (0.01mol), stir for 1h, Add 0.005 mol of dimethylaminoacetaldehyde diethyl acetal dropwise to prepare solution A, and continue to react for 3 hours after dropping. Add 200 mL of ethyl acetate, filter, and add 200 mL of water to the filtrate. Separate the organic layer, extract the aqueous layer with 2×50 mL ethyl acetate, combine the organic layers, wash with water, wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrate to dryness under reduced pressure and recrystallize from acetonitrile / THF to obtain 0.92 g of light yellow solid with a yield of 82.4%.

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Abstract

The invention relates to a preparation method for neratinib. Specifically, N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethyl phosphate-acetamide reacts with 2,2-diethoxy-N,N-dimethylethylamine or 2-(dimethylamino)acetaldehyde in the presence of a lithium salt and an alkali to produce neratinib. The method provided by the invention has the advantages of high yield, mild reaction conditions, usage of common and commercially available reagents, a low price, suitability for industrial production and good economic prospects.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of anticancer drug Neratinib. Background technique [0002] Neratinib is a new oral irreversible, small molecule dual tyrosine kinase inhibitor developed by Wyeth Company of the United States, with a chemical name of (E)-N-[4-[3-chloro-4-(2-pyridine) Methoxy)anilino]-3-cyano-7-ethoxy-6-quinoline]-4-dimethylamino-2-butenamide, the structure of which is shown in formula VI. [0003] [0004] There are two main synthetic routes of Neratinib: Route 1 first forms 3-cyano-6-amino-4-chloro-7-ethoxyquinoline, first introduces side chain V, and then introduces side chain I to obtain Neratinib (JMedChem.2005,48,1107-1131.); Route two is to form 3-cyano-6-acetamido-7-ethoxy-4-chloroquinoline (II) earlier, and first react with side chain I to obtain 3 -cyano-6-acetamido-4-[3-chloro-4-(pyridine-2-methoxy)anilino]-7-ethoxyquinoline (III), after deacetylation of III wi...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 吉民杨加宾王鹏
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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